Chemokines are important for normal immune function and have potent anti-HIV effects. We have been studying cell surface molecules which regulate chemokine structure, secretion and function. Cell surface heparan sulfate proteoglycans have been identified as initial cell binding sites for chemokines with anti-HIV activity and are necessary for efficient blocking by the CC-chemokine RANTES. Cells expressing low levels of proteoglycans show reduced sensitivity to chemokine antiviral effects. Cell surface proteases have been characterized that regulate the activity of chemokines. Protease cleavage of susceptible chemokines results in changes in the structure and receptor specificity of the proteins. The results of these studies indicate that activity of chemokines depends on multiple factors including; the concentration and structure of the chemoattractants, the level of proteoglycan expression, and the number of specific chemokine receptors on target cells.